Deposition of amyloid fibrils in cerebral blood vessels and brain is a histopathologic hallmark of Alzheimer's disease (AD), and amyloid beta (a(beta), the principal component of amyloid fibrils, has been implicated in the neuropathogenesis of AD. A (beta) has been identified also as a soluble peptide (sA(beta) normally present in body fluids. With respect to the origin of A(beta) in cerebral vasculature and brain it has been suggested that A(beta) can be produced locally in brain and/or sA(beta) that normally circulates in plasma and cerebrospinal fluid (CSF) may represent an immediate precursor of A(beta). Recent work indicated blood-brain barrier (BBB) in young/adult rodents may have predominantly anti-amyloidogneic function by favoring degradation of blood borne sA(beta) vs. cerebrovascular sequestration and transport, as well as by participating in the clearance from brain and CSF of CSF-derived peptide. It is no known, however whether the BBB exerts the same role in humans, and whether the BBB transport mechanism to sA(beta) become disregulated by the aging process and in AD patients, as well as in senescent non- human primates that are considered as useful models for studying factors that contribute to the development of cerebral Beta-amyloidosis (rhesus monkey) and/or cerebral amyloid angiopathy, CAA (squirrel monkey). Our pilot data using in vitro transport model of human BBB indicate that adult human brain microvascular endothelial cells (HBMEC) from AD patients retained and transported about 2-fold more intact peptide in comparison to adults, possibly as a result of enhanced endothelial uptake and transcellular transport and/or reduced metabolism of sA(beta) at the BBB. In vivo pharmakinetic-BBB permeability analysis in 1 aged squirrel monkey indicated only moderate plasma clearance and metabolism of circulating sA(beta), significant cortical and leptomeningeal microvascular sequestration of intact peptide, and significant and prefereital cortical BBB uptake of sA(Beta). Present proposal will examine in greater detail the effects of aging BBB mechanisms to A(beta) peptides Studies will be initiated with sA(beta) and sA(beta) by using i) human BBB in vitro transport model from adult, geriatric vs. AD population ; ii) in vivo pharmacokinetic-BBB permeability analysis in adult and aged rhesus (model for cerebral amyloidosis) and squirrel (model for CAA) monkeys. The hypothesis is that during aging, in AD and in senescent non human primates with cerebral amyloidosis and/or CAA, a the BBB is transformed into pro-amyloidgenic transporting membrane predisposing to vascular and/or possibly parenchymal deposition of sA(beta). An ultimate goal is to develop strategies that may reduce vascular and/or parenchymal accumulation of sA(beta) in aged brain and in AD, thereby decelerating and preventing potential cytotoxic effects of sA(beta) and amyloid formation.